KR800000794B1 - Method for preparing low-substituted cellulose ethers - Google Patents

Abstract

Tablet disintegrating agents with excellent binding properties are prepd. by etherification of alk. cellulose contg. free alkali to form a cellulose ether having a degree of substitution of 0.05 - 1.0. The prepn. is dispensed in an aq. soln. contg. 5 - 80 % equiv. acids, followed by adding addnl. acids to neutralize the alkali. Thus, wet pulp was treated with 49 % NaOH followed by propylene oxide. The product was dispersed in a soln. conty. 60 % equiv. HOHc and then 40 % equiv. HOAc wad added to meutralize the product.

Description

Manufacturing method of low substituted cellulose ether

The present invention relates to a process for the preparation of low-substituted cellulose ethers useful as tablet disintegrants, in particular for the production of cellulose ethers having good binding and disintegrating properties.

Conventionally, various kinds of disintegrants have been known. Examples of these disintegrating agents include carboxymethyl cellulose and calcium salts thereof, dried starch, standardized gelatin, alginic acid and calcium salts thereof. These known disintegrants are weak in binding and tend to cause capping in the manufacture of tablets, and the tablets obtained are unsatisfactory because of their relatively high breakage and insufficient disintegration.

In addition to the disintegrants described above, other cellulose ethers having a low degree of substitution are described in Japanese Patent Publication No. 2955/1969, US Patent No. 3,852,421 and UK Patent No. 1,362,700. However, these celluloses were not satisfactory as tablet disintegrants because they had the drawbacks described above.

As a result of intensive studies on cellulose ether having a low substitution degree, the present inventors have found that the performance of cellulose ether as a disintegrating agent largely depends on the specific conditions of the production method of cellulose ether.

Usually, cellulose ethers having a low degree of substitution are produced through each process of conversion to cellulose, esterification of alkali cellulose, neutralization, washing, dehydration, drying and grinding. For example, when the neutralization process is performed by dispersing and dissolving an esterified product containing free alkali in hot or cold water, and then adding a sufficient amount of acid to neutralize all the alkali, the resulting cellulose ether is weakly bound. In the tablet manufacturing process and the following processing, chipping and capping of the tablet are caused and the hardness of the product is insufficient.

On the other hand, in another embodiment, when the neutralization step is performed by dispersing an esterified product containing free alkali in an organic solvent and then adding an acid in the same manner as described in the above examples, the esterification is carried out in an organic solvent. Since it does not dissolve in the water, it remains in a fibrous form, and the fibrous phase remains throughout the following drying and grinding processes. In this case, even if a hammer mill is used as the grinder, it is difficult to pulverize the fibrous dry matter into fine powders, and the resulting product is a fibrous, fluffy powder, and thus poor fluidity. If such fibrous fluff powder is used as a disintegrating agent in the preparation of the tablet mixture, a certain amount of weighing becomes difficult. The poor fluidity of the fibrous fluff cellulose ether powder can be improved by pulverizing with a bowl mill for a long time, but this disadvantageously leads to a decrease in binding properties.

OBJECT OF THE INVENTION The present invention relates to a process for producing cellulose ethers having a low degree of substitution, in which, in addition to tablets, in addition to tablets, the disintegrant has excellent performance, in a fine powder form.

By the method of the present invention, the cellulose ether having a low degree of substitution, that is, a molecular degree of substitution of 0.05 to 1.0, is obtained by esterifying an alkali cellulose with an esterifying agent to obtain a prepared cellulose ether, and all of the prepared cellulose ethers are alkali. A suitable amount of acid to disperse and partially dissolve in an aqueous medium containing from 7 to 70% of acid, which is stoichiometrically required to completely neutralize it, and to neutralize all residual alkali in the aqueous medium. Further, the cellulose ether thus neutralized completely was washed with water, the washed cellulose ether was dried, and the thus prepared cellulose ether was pulverized into a fine powder. Can be.

The esterification process according to the present invention is known. That is, the alkali cellulose containing free alkali is converted into the cellulose ether which has a molecular substitution degree of 0.05-1.0 using the esterification agent of a controlled amount. For example, raw wood pulp, such as wood pulp and rough cotton, immersed in an aqueous 10% to 50% sodium hydroxide solution is pressed to form an alkali cellulose having a NaOH / cellulose about 0.1 to 1.2 weight ratio. This is done by reacting with an esterifying agent such as alkyl chloride or alkylene oxide for 8 hours under stirring in a reactor maintained at a temperature between 90 ° C. The molecular substitution degree needs to be in the range of 0.05 to 1.0, as defined by the number of substituents per anhydrous residue. Cellulose ethers produced when the degree of molecular substitution is outside this range are not suitable as disintegrating agents added to tablets.

Next, with reference to the neutralization step according to the present invention, this step is carried out in two steps instead of a single step as conventionally performed using an inorganic or organic acid.

In the first step neutralizing step according to the present invention, 5 to 80% of the stoichiometric requirement for completely dissolving the alkali bonded to the cellulose in the form of free cellulose ether containing alkali and cellulose in the form of alkali cellulose. Suitably, partially dissolved by dispersion in an aqueous medium containing from 7 to 70% of acid. In this case, the prepared cellulose ether dispersed aqueous medium is made alkaline to partially dissolve the cellulose ether having a molecular substitution degree of 0.05 1.0. Partial dissolution of this cellulose plays a very important role in achieving the object of the present invention. When the amount of acid used in the neutralization step of the first step is outside the above range, the amount of the cellulose ether partially dissolved is too high or too low, so that the final powder type product of the resulting cellulose ether has weak fluidity. Or low binding. In the second stage of the polymerization process, the same or different acid is further added to the partially neutralized mixture to neutralize the alkali remaining after the first stage of neutralization. Since the mixture is not alkaline, the cellulose ether dissolved in the first neutralization step is precipitated again. Partial dissolution and reprecipitation of cellulose ethers by the two-stage neutralization process has excellent fluidity and binding properties, and fine powders that can give satisfactory disintegration to tablets in the next milling step using hammer mill alone. This gives the desired cellulose ether product in the form. The optimum conditions for performing the two-stage neutralization process, including the amount of aqueous medium, the temperature of the prepared cellulose ether dispersion, and the like, may depend on the type of cellulose ether to be obtained.

Neutralization The following washing, dehydration, drying and grinding treatment steps can be carried out by any conventional method.

The reason for the present invention is that a cellulose ether product having excellent detergency is obtained by dissolving the prepared cellulose ether in two parts, that is, in the same aqueous medium as the fibrous part dispersed in the aqueous medium by a two-step polymerization process. This is because the desired cellulose ether, which has been separated into other portions which have been reprecipitated, having both good binding properties and dissolution-good crushability and fluidity by the reprecipitated portion, has advantageous physical properties.

Examples of low-substituted cellulose ethers prepared by the process of the present invention and suitable for use as disintegrants added to tablets are methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxy Ethyl methyl cellulose, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, hydroxybutyl methyl cellulose, hydroxybutyl ethyl cellulose, carboxymethyl cellulose, and salts thereof.

The following examples specifically illustrate the method for the present invention. In these examples, "part" and "%" are attributable to the weight part. Chemical composition and properties of the individual low-substituted cellulose ethers prepared, namely molecular substitution degree, particle size distribution, powder impurity (repose angle, loose apparent density and hard apparent density), respectively, low-substituted cellulose ether The hardness, capping number, disintegration and weight variation of the tablets prepared as follows were measured as follows.

Molecular substitution degree:

The content of the hydroxy group was measured by the iodide of oxo formed from the alkyl iodide liberated by reaction of the alkoxy group with hydroiodic acid. The content of the hydroxyalkoxy group was measured as a product of the oxidative decomposition of the hydroxyalkoxy group with the hot chromic acid.

Particle Size Distribution:

100 g of the sample was stirred in a rotary tapping test sieve stirrer for 20 minutes and subjected to a set of Tyler Standard sieves to determine the distribution in parts by weight.

Powder property:

Japan's Hosoka and Iron Works Powder Tester were used to measure the rest angle, loose apparent density, and solid apparent density.

Hardness of tablets:

It measured with the Erweka tablet hardness tester.

Capping Number:

Twenty tablets to be tested were put in a tablet breaker having a diameter of 27 cm of a rotating drum, which was rotated for 500 (20 minutes), and the number of the chirped or capped tablets was determined by capping water.

Decay Time:

The disintegration time was measured in seconds using water of 37 ± 2 ° C. by the tablet disintegration test method described in the eighth edition of the Japanese Pharmacopoeia.

Number of changes:

The average weight and standard deviation of the weight of 20 tablets were calculated and expressed as a percentage (%).

Example 1

The wood pulp was immersed in 49% aqueous sodium hydroxide solution and then compressed to obtain an alkyl cellulose composed of NaOH 24.1%, Na ₂ CO ₃ 1.7%, cellulose 42.9%, and H ₂ O 31.8%. 100 parts of alkaline cellulose was added to the reactor, and the reactor was filled with nitrogen gas, and then 10.5 parts of propylene oxide was charged. Then, the temperature was gradually increased by stirring for 1 hour at 40 ° C, 1 hour at 50 ° C, and 1 hour at 70 ° C. 110 parts of hydroxypropyl celluloses were obtained. This product was neutralized in three different ways as described below.

Neutralization Ⅰ:

One part of the prepared hydroxypropyl cellulose was dispersed in 2.5 parts of hot water at 60 ° C in a kneader, and stirred at 30 ° C to dissolve completely. Subsequently, a stoichiometric amount, i.e., 0.33 parts of glacial acetic acid, is added to this solution to precipitate cellulose ether containing no fibrous material at all. The cellulose ether thus obtained is referred to as "hydroxypropyl cellulose No. 1" in the following Tables I and II.

Neutralization Ⅱ:

According to the present invention, the acid was neutralized in two steps. The acids used in the first and second steps are hereinafter referred to as primary and secondary acids, respectively. In order to perform the first step neutralization, a solution was prepared by mixing 0.13 parts of glacial acetic acid (the amount corresponds to a stoichiometric amount of about 40%) as a primary acid and 2.5 parts of warm water heated to 65 ° C together in a kneader. To the dilute acetic acid solution thus obtained was added 1 part of the prepared ether and dispersed. Then, this dispersion was kept at 30 degreeC, and all the prepared cellulose ethers were dissolved. Thereafter, 0.20 part of glacial acetic acid (this amount corresponds to a stoichiometric amount of about 60%) as a secondary acid was added to obtain a fibrous substance containing reprecipitated cellulose ether. The cellulose ether thus obtained is referred to as "hydroxypropyl cellulose No. 2" in Tables I and II.

Neutralization Ⅲ:

The same procedure as described for the neutralization II was carried out, except that 0.20 parts of the primary acid and the amount of the secondary acid corresponding to stoichiometric quantities of about 60% were reduced to 0.13 parts. The cellulose ether thus obtained was referred to as "hydroxypropyl cellulose No. 3" in Tables I and II.

The hydroxypropyl cellulose products were each washed with hot water heated to 80 ° C., filtered, dried and ground under a high speed hammer to obtain a powder. Each hydroxypropyl cellulose had a molecular substitution degree of about 0.28 of the hydroxypropyl group. Particle size distribution and powder characteristics are shown in Table I.

[Table I]

* Control

Next, a purification test was performed for each of the hydroxypropyl cellulose Nos. 1, 2, and 3 as a disintegrating agent, and at the same time, a test without a disintegrating agent was performed. This test was carried out by direct compression by operating under 45 r.p.m. and 1-ton pressure using a rotary purifier model HT-P-18 manufactured by Hada Iron Works, Japan, equipped with a punch having a diameter of 9 mm and a curvature of 10 mm. The physical properties of the preparations of the tablets to be tested and the tablets thus obtained are shown in Table II.

Table II

* Control

Example 2

The wood pulp was immersed in 40% aqueous sodium hydroxide solution and then compressed to obtain alkali cellulose composed of NaOH 19.9% Na ₂ CO ₃ 1.0%, cellulose 46.9% and H ₂ O 32.2%. 100 parts of alkaline cellulose were added to the reaction bath, nitrogen gas was charged into the vessel, and 15 parts of methyl chloride were introduced. Then, the esterification reaction was gradually carried out at 40 ° C. for 2 hours, at 50 ° C. for 1 hour and at 80 ° C. for 1 hour. The mixture was stirred with increasing the temperature to obtain 113 parts of the crude esterified product. This product was neutralized in two different ways as described below.

Three parts of the prepared cellulose ether were dispersed and neutralized in a mixer in a mixed solvent of 20 parts of water containing 80 parts of methanol and stoichiometric amount of 35% hydrochloric acid, that is, 0.20 parts. In this case, dissolution of cellulose ether does not occur. The neutralized product became fibrous. The cellulose ether thus obtained is referred to as "methyl cellulose No. 1" in the following Tables III and IV.

Chinese Ⅴ:

One part of the prepared cellulose ether was dispersed in four parts of water heated to 65 ° C containing 0.02 parts of 35% hydrochloric acid (corresponding to a stoichiometric amount of about 10%) as the primary acid in the kneader. Next, this dispersion was kept at 30 ° C to dissolve the crude cellulose ether. Next, 0.18 part of 35% hydrochloric acid was added as a 2nd lane, and the fibrous substance containing cellulose ether reprecipitated starch was obtained. The cellulose ether thus obtained was referred to as "methyl cellulose No. 2" in Tables III and IV.

Each of the methyl cellulose products obtained above was washed with water heated to about 80 ° C., filtered, dried and ground with a high speed hammer mill to obtain a fine powder. The particle size distribution and powder characteristics of each methyl cellulose are shown in Table III. In this table, methyl cellulose Na.1a is obtained by further pulverizing methylcellulose No. 1 in a vibration mill in order to increase its fluidity. The molecular substitution degree of the methoxy group in each methyl cellulose was 0.48.

Table III

* Control

Next, the methyl cellulose Nos. Purification tests were performed on 1, 1a and 2, respectively. In each test (T-5, T-6 or T-7) a tablet containing the same composition, 100 parts of lactose, 10 parts of disintegrant, 0.5 parts of magnesium stearate and 0.5 parts of talc was used. The method and conditions of the tablet formulation were the same as in Example 1. Table IV shows the physical properties of the tablets prepared.

[Table IV]

* Control

Example 3

The wood pulp was immersed in 35% aqueous sodium hydroxide solution and then compressed to give alkali cellulose comprising NaOH 18.5%, Na ₂ CO ₃ 0.7%, cellulose 43.6% and H ₂ O 37.2%. 100 parts of this alkaline cellulose was added to the reaction vessel, filled with nitrogen gas, and then 10 parts of ethylene oxide was introduced, and the esterification reaction was gradually increased for 1 hour at 30 ° C, 1 hour at 35 ° C, and 1 hour at 70 ° C. While stirring, 108 parts of crude esterified products were obtained. This product is dispersed in a mixer in 1,600 parts of hot water heated to 80 ° C. containing 5.5 parts of glacial acetic acid (corresponding to a stoichiometric amount of about 20%) as the primary acid and glacial acetic acid as a secondary acid in an amount sufficient to complete neutralization. Part was dissolved partially after addition. As a result, a fibrous material containing the reprecipitated portion of the cellulose ether was obtained. The hydroxyethyl cellulose product thus prepared was washed with warm water heated to 80 ° C., filtered and dried, and then ground with a high speed hammer mill to obtain a fine powder. This hydroxyethyl cellulose had a molecular degree of substitution of a hydroxyethoxy group of 0.35, and the particle size distribution and powder characteristics thereof are shown in Table V.

[Table V]

Next, the purification test was performed using said hydroxyethyl cellulose as a disintegrating agent, and the control test was performed using the conventional disintegrating agent instead of hydroxy ethyl cellulose. The test was carried out by the hydration-granulation tablet method as follows. 50 parts of lactose, 45 parts of phenathetin, and 5 parts of disintegrating agent are mixed with high content containing 1.7 parts of polyvinylpyrrolidone in a super-mixer to control moisture. It was granulated with granules having a particle size distribution that remained without passing through the meshive. After drying, 100 parts of this granule were mixed with 0.5 parts of magnesium stearate and 0.5 parts of talc, and the mixture was prepared under the same conditions as in Example 1, but the pressure was increased from 1 to 1.5 tons. The physical properties of the tablets thus prepared are shown in Table VI.

[Table VI]

* contrast

Claims (1)

Alkali cellulose is esterified in the presence of an esterifying agent to obtain crude cellulose ether, and the crude cellulose ether contains an acid corresponding to 5 to 80% of the amount stoichiometrically required to neutralize all alkalis. Partially dissolved by dispersing in the medium, acid was added to the aqueous medium to neutralize any remaining alkali, and the fully neutralized cellulose ether was washed with water, dried, and then triturated into fine powder to give a molecular substitution of 0.05. The method of manufacturing the low substituted cellulose ether which is -1.0.